Seven new oxime-based acetylcholinesterase reactivators were compared with three currently available ones (obidoxime, trimedoxime, HI-6) for their ability to lessen cholinesterase inhibition in blood and brain of cyclosarin-treated rats. Oximes were given at doses of 5% their LD(50) along with 21 mg/kg atropine five min before the LD(50) of cyclosarin (120 ug/kg) was administered. Blood and brain samples were collected 30 minutes later. The greatest difference between acetylcholinesterase inhibition in blood of cyclosarin-treated rats was found after administration of HI-6 (40%), compared to 22% for trimedoxime and 6% for obidoxime. Only two of the seven newly synthesized oximes had any effect (K203 at 7%, K156 at 5%). Effective oximes against cyclosarin-inhibited plasma butyrylcholinesterase were HI-6 (42%), trimedoxime (11%), and K156 (4%). The oximes were less effective in brain than in blood, with reactivation values for HI-6 30% against acetylcholinesterase and 10% against butyrylcholinesterase. Values for newly synthesized oximes were less than 10% for K206, K269 and K203.

• Klíčová slova
• acetylcholinesterase, butyrylcholinesterase, cyclosarin, oximes, reactivators,
• MeSH
• acetylcholinesterasa krev   metabolismus   MeSH
• atropin farmakologie   MeSH
• krysa rodu Rattus MeSH
• mozek účinky léků   enzymologie   MeSH
• organofosforové sloučeniny toxicita   MeSH
• oximy chemie   farmakologie   MeSH
• potkani Wistar MeSH
• reaktivátory cholinesterasy chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• atropin MeSH
• cyclohexyl methylphosphonofluoridate MeSH Prohlížeč
• organofosforové sloučeniny MeSH
• oximy MeSH
• reaktivátory cholinesterasy MeSH

INTRODUCTION: Organophosphorus nerve agents inhibit the enzyme, acetylcholinesterase (AChE; EC 3.1.1.7). AChE reactivators (also known as oximes) are generally used for the reactivation of an inhibited enzyme. METHODS: Two new AChE reactivators--K033 and K027--were tested for their in vitro reactivation of sarin-inhibited pig-brain AChE. Their reactivation potencies were compared with the commercially available AChE reactivators, pralidoxime, obidoxime, and HI-6. RESULTS: Of the oximes tested, the newly developed oxime K027 achieved the highest reactivation potency (100%; concentration of the oxime -10(-2) M). However, oxime HI-6 (33%) and obidoxime (23%) seem to be the best AChE reactivators for human relevant doses (10(-4) M and lower). CONCLUSION: For human relevant doses, newly developed oximes (K027 and K033) do not surpass the reactivation potency of the most promising oxime, HI-6.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota farmakologie   MeSH
• cholinesterasové inhibitory toxicita   MeSH
• mozek účinky léků   enzymologie   MeSH
• obidoxim chlorid farmakologie   MeSH
• oximy farmakologie   MeSH
• pralidoximové sloučeniny farmakologie   MeSH
• prasata MeSH
• pyridinové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterasy farmakologie   MeSH
• sarin toxicita   MeSH
• techniky in vitro MeSH
• výzkumný projekt MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Prohlížeč
• 1,4-bis(2-hydroxyiminomethylpyridinium)butane MeSH Prohlížeč
• acetylcholinesterasa MeSH
• antidota MeSH
• asoxime chloride MeSH Prohlížeč
• cholinesterasové inhibitory MeSH
• obidoxim chlorid MeSH
• oximy MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy MeSH
• sarin MeSH

Oximes in combination with atropine, are an integral part of the treatment of acute intoxications with organophosphorus insecticides or with the nerve agents such as tabun, sarin, soman, cyclosarin or VX. Organophosphorus compounds are extremely potent inhibitors of the enzyme acetylcholinesterase (AChE, 3.1.1.7). The pharmacological action of oximes is multiple: they are able to reactivate the inhibited AChE, but they affect acetylcholine release in peripheral and central cholinergic synapses, allosterically modulate the muscarinic receptors in peripheral and central synapses, and influence the nicotinic receptor-associated ion-channels. In our study, we have determined the acute toxicity of different structures of oximes after intramuscular application in mice. The acute toxicity of oximes is crucial for the assesment of a dose applied as a treatment for organophosphorus intoxications. We have tested 7 oximes of different structures (HS-6, K033, BI-6, MMB-4, K048, HI-6 and obidoxime ) and during our experiments we have observed the intoxication process including typical signs of intoxication, and times of death. K033 was the most toxic oxime with an LD50 of only 48 mg/kg, while the least toxic oxime - HI-6 - has an LD50 value of 671 mg/kg. All the oximes tested were of the bispyridinium type, with different length or shape of the connecting chain and positions of oxime groups at the pyridinium rings. All these structural features play an important role in biological activity of these compounds performed by their acute toxicity as well as by their reactivation potency.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• myši MeSH
• reaktivátory cholinesterasy aplikace a dávkování   chemie   toxicita   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• reaktivátory cholinesterasy MeSH